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Open Access Highly Accessed Research article

A gene expression signature of RAS pathway dependence predicts response to PI3K and RAS pathway inhibitors and expands the population of RAS pathway activated tumors

Andrey Loboda1, Michael Nebozhyn1, Rich Klinghoffer2, Jason Frazier2, Michael Chastain2, William Arthur2, Brian Roberts2, Theresa Zhang3, Melissa Chenard3, Brian Haines3, Jannik Andersen3, Kumiko Nagashima3, Cloud Paweletz1, Bethany Lynch1, Igor Feldman1, Hongyue Dai2, Pearl Huang4 and James Watters1*

Author Affiliations

1 Department of Molecular Profiling and Research Informatics, Merck Research Laboratories, West Point, Pennsylvania 19486, USA

2 Rosetta Inpharmatics LLC, a wholly-owned subsidiary of Merck & Co., Inc, Seattle, Washington 98109, USA

3 Oncology basic research, Merck Research Laboratories, 33 Avenue Louis Pasteur Boston, MA, USA 02115

4 Oncology, Merck Research Laboratories, North Wales, Pennsylvania, 19454, USA

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BMC Medical Genomics 2010, 3:26  doi:10.1186/1755-8794-3-26

Published: 30 June 2010

Abstract

Background

Hyperactivation of the Ras signaling pathway is a driver of many cancers, and RAS pathway activation can predict response to targeted therapies. Therefore, optimal methods for measuring Ras pathway activation are critical. The main focus of our work was to develop a gene expression signature that is predictive of RAS pathway dependence.

Methods

We used the coherent expression of RAS pathway-related genes across multiple datasets to derive a RAS pathway gene expression signature and generate RAS pathway activation scores in pre-clinical cancer models and human tumors. We then related this signature to KRAS mutation status and drug response data in pre-clinical and clinical datasets.

Results

The RAS signature score is predictive of KRAS mutation status in lung tumors and cell lines with high (> 90%) sensitivity but relatively low (50%) specificity due to samples that have apparent RAS pathway activation in the absence of a KRAS mutation. In lung and breast cancer cell line panels, the RAS pathway signature score correlates with pMEK and pERK expression, and predicts resistance to AKT inhibition and sensitivity to MEK inhibition within both KRAS mutant and KRAS wild-type groups. The RAS pathway signature is upregulated in breast cancer cell lines that have acquired resistance to AKT inhibition, and is downregulated by inhibition of MEK. In lung cancer cell lines knockdown of KRAS using siRNA demonstrates that the RAS pathway signature is a better measure of dependence on RAS compared to KRAS mutation status. In human tumors, the RAS pathway signature is elevated in ER negative breast tumors and lung adenocarcinomas, and predicts resistance to cetuximab in metastatic colorectal cancer.

Conclusions

These data demonstrate that the RAS pathway signature is superior to KRAS mutation status for the prediction of dependence on RAS signaling, can predict response to PI3K and RAS pathway inhibitors, and is likely to have the most clinical utility in lung and breast tumors.